Treatment of Severe Sepsis—An Advance At Last!
Abstract & Commentary
Synopsis: Therapy with drotrecogin alfa activated (DRA—Zovant), a recombinant human activated protein C, was associated with significantly improved survival in patients with severe sepsis.
Source: Bernard GR, et al. N Engl J Med. 2001;344:699-709.
Bernard and colleagues, in a double-blind, placebo- controlled trial, randomized 1690 patients with severe sepsis at 164 centers in 11 countries to receive adjunctive therapy with either placebo or drotrecogin alfa activated (DRA—ZovantÔ), a recombinant human activated protein C (aPC). Patients were eligible for randomization if they had known or suspected infection with 3 or more signs of systemic inflammation and sepsis-induced organ dysfunction of no more than 24 hours duration; treatment was initiated within 24 hours of having met inclusion criteria. DRA was given intravenously as a continuous infusion at a dose of 24 mg/kg/h for 96 hours. The infusion was temporarily interrupted 1 hour before percutaneous procedures or major surgery and was resumed, respectively, 1 and 12 hours later. Other therapies, including fluids, antibiotics, vasopressors, etc., were not specified by protocol. The primary efficacy end point was death from any cause by 28 days after the start of the infusion.
Protein C deficiency was detected in 87.6%, plasma d-dimer was present in 99.7%, and IL-6 in 98.5%. At 28 days, the all-cause mortality was 30.8% in the placebo group and 24.7% in the DRA recipients (P = .005). The reduction in relative risk of death was 19.4% (95% CI, 6.6-30.5%). Plasma d-dimer and IL-6 levels were significantly lower through day 7 in DRA recipients.
The overall incidence of serious adverse events was similar in the 2 groups, although serious bleeding occurred in 3.5% of DRA and only 2.0% of placebo recipients (P = .06). Fatal intracranial hemorrhage occurred in 2 DRA recipients during infusion and in 1 placebo recipient 6 days after the end of infusion. Neutralizing antibody against aPC was not detected.
Comment by Stan Deresinski, MD, FACP
This trial, the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis study (PROWESS) was terminated on June 28, 2000, prior to completion of the total planned enrollment at the time of a scheduled interim analysis when it became apparent that statistical significance had been reached. Given the repeated failure of similar trials in the treatment of severe sepsis, even some of the investigators were probably surprised to find something that worked.
Severe sepsis is associated with a procoagulant, as well as a generalized inflammatory response.1,2 The procoagulant state in sepsis may result in the depletion of 1 or more of the 3 primary endogenous inhibitors of coagulation: aPC, antithrombin III, and tissue factor pathway inhibitor. The activation of protein C, which normally occurs in the microcirculation following the binding of thrombin to the endothelial receptor thrombomodulin, is a critical defense mechanism against excess fibrin formation.3
Sepsis may cause impairment of the conversion of protein C to the activated state as a result of decreased production of thrombomodulin in response to proinflammatory cytokines. As a consequence, the majority of septic patients have reduced protein C levels and there is an association between increased mortality and the extent of protein C depletion.4 In patients with meningococcemia, failure of this system is associated with the development of purpura fulminans. In fact, the administration of a protein C concentrate was associated with improved survival, relative to matched historical controls, in patients with severe meningococcemia.5
Restoration of balance in the coagulation system is, however, probably not the only reason for the efficacy of DRA: aPC also inhibits monocyte production of IL-1b and TNF-a in response to exposure to lipopolysaccharide.6 It also inhibits LPS-induced nuclear translocation of NFkB, inhibits neutrophil activation, downregulates the expression of several endothelial cell adhesion molecules, including ICAM-1, E-selectin, and VCAM-1.7
Bernard et al have demonstrated the efficacy of aPC infusion in patients with severe sepsis. Now the challenge will be to learn how to optimally use this advance in therapy.
References
1. Cate H. Crit Care Med. 2000;28(9 Suppl):S9-11.
2. Esmon C. Crit Care Med. 2000;28(9 Suppl):S44-48.
3. Taylor FB Jr, et al. Blood. 2000;95:1680-1686.
4. Mesters RM, et al. Crit Care Med. 2000;28:2209-2216.
5. White B, et al. Blood. 2000;96:3719-3724.
6. Schmidt-Supprian M, et al. Eur Cytokine Netw. 2000; 11:407-413.
7. White B, et al. Br J Haematol. 2000;110:130-134.
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